May 29, 2018 PAP-Q2-18-FA-002
In order for contract development and manufacturing organizations (CDMOs) to bring drugs to the market, a foundation of flexibility is crucial.1 Multiple operations can be leveraged in support of drug discovery; as more complicated drugs are being formulated, drug manufacturing has also grown more complex. One-size-fits-all operations are a thing of the past, instead companies must diversify.1 For a CDMO to remain truly competitive, multiple systems must be at play.
One way to ensure flexibility is building it into facilities. Manufacturing organizations that are looking to expand into cell and gene therapy and next-generation therapies benefit from diversifying their operations design. As Peter Walters, Lead Process Engineer from CRB USA, explained to Pharma’s Almanac: “Constructing a process map for all of the intended processes in the facility from an operational perspective can be a key tool for communicating process requirements. Specific requirements for each process — equipment, material flows, personnel movements, etc. — must be considered.”2
In order to confirm the safety of a multi-product facility, controls are needed to segregate and fully contain these processes from all other areas of the facility.2 “For multi-product facilities, processing of multiple gene vectors should be performed either on a temporally segregated campaign basis (with sanitization between) or in parallel but in completely segregated viral production spaces for each product campaign produced,” advised Walters.2
Single-use technology has been around for over 20 years, and primarily functioned as a means to achieve clinical batch and pilot-scale operations. However, as demand for bioprocessing has grown, this technology has likewise grown in demand. It is seen as an attractive option for a number of reasons.3 Employing single-use eliminates cleaning, and cleaning validation steps, which reduces the risk of contamination.3 Single-use technology also allows faster turnover from one product to another, reduces water consumption, allows small scale commercial production and gives a facility the ability to run multiple molecules in conjunction.4 Single-use systems are also able to connect two unit operations.4 Speaking to industry publication Pharmaceutical Technology, Miriam Monge, Director of Process Development and Bioprocess Platforms, Integrated Solutions at Sartorius Stedim Biotech, noted the versatility of molecules that can be manufactured using this process. “Antibodies, proteins, vaccines, cell therapy, and gene therapy all fall into categories of molecules that can benefit from being manufactured in fully single-use, end-to- end processes,” said Monge of these next generation therapies.4
Of course, single-use is not without its own set of challenges. In the same interview, Steve Miller, Global Head of Next Generation System Development, Life Science, Upstream and Systems Business Field Millipore S.A.S., spoke on issues related to the technology. “Implementing single-use brings with it new challenges that traditional facilities do not face, such as ensuring skids from different vendors have compatible connectors and common spare components such as clamps. Other, lesser-known challenges are related to packaging, installation and disposal, as each manufacturer may have different approaches, making operator life more complex and introducing opportunities for more errors.” Indeed, even single-use technology, though decades old at this point, has yet to be entirely perfected.4
Manufacturing for next-generation therapies is inherently challenging on multiple fronts and has challenged the way the industry produces drugs on all levels. Perhaps this is felt most acutely in the push for operations to transition from batch to continuous. Whereas batch manufacturing is burdened by the previously defined maximum asset utilization available, companies have been generally risk-averse in migrating from this model.1 In continuous manufacturing, a product can be monitored continuously. If there is an issue, it is likely that it will be noticed in real time, leading to overall improvement.3
Perhaps the greatest ally of continuous manufacturing is the FDA. The process has been championed by the regulating body, and is considered a fast and efficient means of achieving production, especially when compared to batch processing.5 The agency has identified continuous as a means to improve product quality, as there is hope that continuous processing will lead to the identification of the root causes of drug shortages or recalls.5 Though the agency has recognized the challenging nature of transitioning to continuous, it is greatly encouraged.
Sau (Larry) Lee, Ph.D., Deputy Director of the Office of Testing and Research, and Chair of the Emerging Technology Team, Office of Pharmaceutical Quality, CDER, described the benefits of making the transition in an article which appears on the FDA website, titled: “Modernizing the Way Drugs Are Made: A Transition to Continuous Manufacturing.”5 In contrast to batch, with continuous manufacturing, pharmaceuticals move nonstop through the manufacturing facility which speeds up processes by getting rid of hold times. “Material is fed through an assembly line of fully integrated components. This method saves time, reduces the likelihood for human error, and can respond more nimbly to market changes. To account for higher demand, continuous manufacturing can run for a longer period of time, which may reduce the likelihood of drug shortages,” wrote Lee.5
The challenge of continuous is largely based on old processing systems. The cost associated with totally renovating a plant is prohibitive, especially as most manufacturing facilities are entirely outfitted for batch processing. In spite of this, the long-term cost-benefit will outweigh the challenge of a high start-up cost, and presents the opportunity for significant monetary savings.5 Although continuous is practiced in the chemical and petrochemical industries, the technology for biopharmaceutical continuous processing is still in its infancy.5
The Bioprocessing Summit, taking place this year, will address this challenge and its potential for biopharmaceuticals specifically. Topics covered at the 4th Annual Continuous Processing in Biopharm Manufacturing will include integrated continuous processing, continuous processes for novel biotherapeutics, upstream perfusion processes, new technologies and approaches and economics in innovative manufacturing.6 The FDA has partnered with the Biomedical Advanced Research and Development Authority, a program within the U.S. Department of Health and Human Services, in order to support both the research and funding of continuous manufacturing for biopharma. The agency has also taken steps to train staff and conduct internal research on any risk areas associated with the process, in order to evaluate like technology.5
To stay ahead of trends in the industry, manufacturing companies must not only plan for the next generation of pharmaceuticals but also for the next generation of manufacturing. All things considered, this will include a transition towards or fully incorporating 3D printing in operations. This new means of production could entirely revolutionize the industry. According to Leroy Cronin, a Chemist at the University of Glasgow in the United Kingdom, who was able to digitize chemistry in a standalone 3D printed device, creating 3D printed pharmaceuticals will democratize drug making.7 For Cronin, one of the possibilities of 3D printed medicine includes “the on-demand production of chemicals and drugs that are in short supply, hard to make at big facilities, and allow[s] customization to tailor them to the application.”7 Cronin’s device was “designed and constructed by using a chemical to computer-automated design (ChemCAD) approach that enables the translation of traditional bench-scale synthesis into a platform-independent digital code,” read his abstract.8 This code was able to guide the synthesis of four different chemical reactions, from filtering to evaporating solutions, in a total of 12 steps.7
3D printing applied to pharmaceuticals has tremendous potential. Research firm MarketsandMarkets estimates that by just 2020, the 3D printing of medicines could capture a total market value of approximately $2.13 billion.9 This technology has the potential to impact the industry on all levels, from creating unique dosage forms and complex drug release profiles to the printing of living tissue. 9
In order to successfully manufacture drugs into the next generation — whatever form that takes — CDMOs must embrace Industry 4.0. Industry 4.0 encompasses the methods for smarter production, including information technology–integrated facilities that are better able to capture data in real time, thereby improving processes. The next generation of manufacturing will be data-centric.1 The goal of bettering facilities and operations is to reduce waste and increase the production of quality drugs, reliably. However it is implemented, Industry 4.0 will be a prime driver into the next ten years, and must be integrated into operations as a way to keep up with the next generation of drugs, and the manufacturing that is required to supply them.
From planning a facility so it that operations can be segregated, to bettering single-use technology and ultimately moving from batch to continuous manufacturing, to embracing the opportunity of 3D printing and what that means for the industry, drug manufacturing is at an crucial moment, and ultimately, the companies who encourage and build innovation into their operations are at an advantage when it comes to meeting the growing needs of the next generation.
Dr. Challener is an established industry editor and technical writing expert in the areas of chemistry and pharmaceuticals. She writes for various corporations and associations, as well as marketing agencies and research organizations, including That’s Nice and Nice Insight.